1. Field of the Invention
The present invention discloses a method and composition for the topical treatment of streptococcal infections by the use of a lysin enzyme blended with a carrier suitable for topical application to dermal tissues.
2. Description of the Prior Art
The genus Streptococcus is comprised of a wide variety of both pathogenic and commensal gram-positive bacteria which are found to inhabit a wide range of hosts, including humans, horses, pigs, and cows. Within the host, streptococci are often found to colonize the mucosa surfaces of the mouth, nares and pharynx. However, in certain circumstances, they may also inhabit the skin, heart or muscle tissue.
Pathogenic streptococci of man include S. pyogenes, S. pneumoniae, and S. faecalis. While Group A streptococci can be present in the throat or on the skin and cause no symptoms of disease, they may also cause infections that range from mild to sever and even life-threatening. Among the pathogenic hemolytic streptococci, S. pyogenes, or group A streptococci have been implicated as the etiologic agent of acute pharyngitis "(strep throat"), impetigo, rheumatic fever, scarlet fever, glomerulonephritis, and invasive fasciitis. Necrotizing fasciitis (sometimes described by the media as "the flesh-eating bacteria") is a destructive infection of muscle and fat tissue. Invasive group A streptococcal infections occur when the bacteria get past the defenses of the person who is infected. About 10,000 to 15,000 cases of invasive GAS disease occur in the United States each year resulting in over 2,000 deaths. CDC estimates that 500 to 1,500 cases of necrotizing fasciitis and 2,000 to 3,000 cases of streptococcal toxic shock syndrome occur each year in the United States. Approximately 20% of patients with necrotizing fasciitis die, and 60% of patients with streptococcal toxic shock syndrome die. About 10 to 15% of patients with other forms of invasive group A streptococcal disease die.
Additionally, Group C Streptococcus can cause cellulitis from skin breaks, although cellulitis is normally associated with Staphylococcus aureus. Cellulitis can result in death, particularly in older individuals or in individuals who are already weakened.
The first individual to identify the serological and immunological groups of streptococci was Dr. Rebecca Lancefield, (Lancefield, R. C., "A Serological Differentiation of Human and other Groups of Hemolytic Streptococci," J. Exp. Med., Vol.57, pp 571-595 1933), after whom the grouping system was named. The group A streptococcus was identified on the basis of B-1, 4 N-acetylglucosamine terminal sugar moieties on a repeating rhamnose sugar backbone found as part of the structure of the organism's cell wall. Antiserum raised against group A streptococci and subsequent absorptions to remove cross-reactions were shown to specifically react with the cell wall component of these organisms and became the grouping antisera for group A streptococci. A number of methods have been devised to fragment the group A streptococcal cell wall carbohydrate. These methods include heating by boiling at pH 2.0, autoclaving, trichloroacetic acid extraction, hot formamide digestion, nitrous acid extraction and enzyme digestion by enzymes derived from the soil microorganisms of species streptomyces, and the phage-associated enzyme lysin. Each of these methods have various advantages and disadvantages.
The rapid diagnosis of group A streptococcal pharyngitis has become more readily available to both physicians and clinical laboratories by replacing time consuming culturing methods requiring a minimum of 24 to 72 hours to identify the presence of group A streptococci with a rapid antigen-antibody test capable of being performed and read in less than one hour. Culturing methods vary in the degree of sensitivity of detection. In one case, a simple 5% sheep blood agar plate may be used in conjunction with a Bacitracin disc and culturing 24 hours at 37 degree(s) C. aerobically to identify group A streptococci. Alternatively, selective media and anaerobic conditions may be used to inhibit overgrowth by other organisms and incubation at 35 degree(s) C. for a minimum of 48 hours. In addition, depending on the transport media, the delay in testing, and any antibacterial agents that the patient may have taken, culturing may result in nonviable organisms that fail to grow in the media although the patient is indeed colonized by the group A streptococcus. In the latter case a sensitive immunoassay for group A streptococcal antigen can detect these nonviable organisms.
In the past, antibiotics were used to treat Streptococcal infections. U.S. Pat. No. 5,260,292 (Robinson et al.) discloses the topical treatment of acne with aminopenicillins. The mouth and composition for topically treating acne and acneiform dermal disorders includes applying an amount of an antibiotic selected from the group consisting of ampicillin, amoxicillin, other aminopenicillins, and cephalosporins, and derivatives and analogs thereof, effective to treat the acne and acneiform dermal disorders.
U.S. Pat. No. 5,409,917 (Robinson et al.) discloses the topical treatment of acne with cephalosporins.
Neither of these applications specifically call for the treatment of streptococcal infections, nor do they address the problems of streptococcal cellulitis or necrotizing fasciitis. Additionally, the use of these antibiotics are presenting new problems. Specifically, a growing number of people are allergic to penicillin, one of the primary antibiotics used to treat Streptococcal infections. Even when penicillin can be used, penicillin resistant strains of Staphylococcal aureus which may be present in the organism can produce penicillinase, which can destroy the penicillin before it has time to act on the Streptococcus. Erythramycin can be used to treat Streptococcal infections; however, 20-30% of Streptococcus are resistant to erythramycin. Also, it is hypothesized that some streptococcus can lie dormant for up to ten days; cells which are not reproducing will not be killed by traditional antibiotics.
Consequently, other efforts have been sought to first identify and then kill Streptococcus.
Maxted, (Maxted, W. R., "The Active Agent in Nascent Phage Lysis of Streptococci," J. Gen Micro, vol 16, pp 585-595 1957), Krause, (Krause, R. M., "Studies on the Bacteriophages of Hemolytic Streptococci," J. Exp Med, vol 108, pp 803-821, 1958), and Fischetti, (Fischetti, V. A., et al, "Purification and Physical Properties of Group C Streptococcal Phage Associated Lysin," J. Exp Med, Vol 133 pp 1105-1117 1971), have reported the characteristics of an enzyme produced by the group C streptococcal organism after being infected with a particular bacteriophage identified as C1. The enzyme was given the name lysin and was found to specifically cleave the cell wall of group A, group C and group E streptococci. These investigators provided information on the characteristics and activities of this enzyme with regard to lysing the group A streptococci and releasing the cell wall carbohydrate. They never reported on the utility of this enzyme in an immunological diagnostic test for the detection of group A streptococci from throat swabs in patients. The failure to use this enzyme for a clinical diagnostic test was due to a number of problems associated with the enzyme such as: the difficulty in growing large amounts of bacteriophage in the group C streptococci, the time delays in inactivating the residual enzyme when trying to obtain phage stocks, the instability of the enzyme itself to oxidative conditions and heat, and nonspecific reactions in immunoassays performed in the presence of other organisms and the biological components in the sample.
U.S. Pat. No. 5,604,109 (Fischetti et al.) teaches the rapid and sensitive detection of group A streptococcal antigens by a diagnostic test kit which utilizes a sampling device consisting of a throat swab made of synthetic or natural fibers such as Dacron or rayon and some type of shaft which holds the fibers, is long enough to place the fibers in the tonsillar area and is capable of being used to swab the area to remove sufficient numbers of colonizing or infecting organisms. The swab can then be placed in the enzyme extraction reagent and subsequently used in an immunoassay. The invention can comprise a test kit for detecting Group A streptococci, containing the lysin enzyme for releasing Group A streptococcal components, and a ligand capable of binding with a component of the Group A streptococcus.
U.S. patent (application Ser. No. 08/962,523) (Fischetti, et. al.) and U.S. patent (application Ser. No. 09/257,026) (Fischetti et al.) disclose the use of an oral delivery mode, such as a candy, chewing gum, lozenge, troche, tablet, a powder, an aerosol, a liquid or a liquid spray, containing a lysin enzyme produced by group C streptococcal bacteria infected with a C1 bacteriophage for the prophylactic and therapeutic treatment of Streptococcal A throat infections, commonly known as strep throat.
None of the prior art suggests the use of the lysin enzyme for the treatment of topical or dermatological infections.